The molecular structures of new chemical entities are becoming more complex leading to drugs with low aqueous solubility and dissolution rate limited absorption after oral administration, still the preferred route of drug administration. Considering the fact that many newly synthesized molecules are poorly soluble in aqueous environment, converting these compounds into useful therapeutics remains challenging. Techniques that have commonly been used to improve dissolution and bioavailability of poorly water-soluble drugs in general, include micronization, the use of surfactants, and the formation of solid dispersions.
Six types of drug-carrier interactions in solid state dispersions were already outlined in literature: simple eutectic mixtures, solid solutions, glass solutions, glass suspensions, amorphous precipitates in a crystalline carrier and compound or complex formation. Other factors such as increased wettability, solubilization of the drug by the carrier at the diffusion layer, and the reduction or absence of aggregation and agglomeration may also contribute to increased dissolution.
Drugs having a dissolution-limited oral absorption might benefit from a reduction in particle size, as pointed out in the following equation that is a modification of the well-known Noyes-Whitney relation:
where dM/dt is the dissolution rate, A the specific surface area of the drug
            ⅆ      M              ⅆ      t        =            A      ⁢                          ⁢              D        ⁡                  (                                    C              s                        -                          C              t                                )                      h  particle, D the diffusion coefficient, h the diffusion layer thickness, Cs the saturation solubility, and Ct the drug concentration at time t. Since the surface area increases with decreasing particle size, higher dissolution rates may be achieved through the reduction of the particle size of drug substances. This effect has been highlighted by the superior dissolution rates after micronisation of certain sparingly water soluble drugs as opposed to regularly milled forms. However, particle size reduction does not necessarily always result in the expected improvement in dissolution rate. This effect arises as a result of the decrease of the effective surface area due to agglomeration and aggregation of very fine particles due to the increased surface energy and subsequent stronger van der Waals' attraction between non-polar molecules. Therefore, the surface of the particles needs to be protected from agglomeration.
U.S. Pat. No. 5,145,684 discloses particles consisting essentially of 99.9 to 10% by weight of a crystalline drug substance having a solubility in water of less than 10 mg/ml, said drug substance having a non-crosslinked surface modifier adsorbed an the surface thereof in an amount of 0.1 to 90% by weight and sufficient to maintain an effective average particle size of less than about 400 nm. In particular it discloses a modified steroid A aqueous dispersion, comprising 5% steroid A, with a particle size distribution ranging from about 68 to 520 nm and a number average particle size of 204 nm.
U.S. Pat. No. 5,503,723 discloses refining a nanoparticle dispersion by placing it between two electrodes and applying an electric field between said electrodes, wherein the dispersion consists essentially of particles of poorly soluble crystalline therapeutic or diagnostic agent, wherein 99% of the particles have a particle size below 400 nm and are associated with a surface modifier which is capable of stabilizing the nanoparticles. In particular, it describes a danazol dispersion wherein 10% of the particles are reduced in size down to 180 nm.
U.S. Pat. No. 5,858,410 discloses a drug carrier, prepared using the jet stream principle and using surfactants such as Tween 80 and mannitol, comprising particles of a therapeutic agent which is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein the therapeutic agent has an average diameter below 1,000 nm and the proportion of particles larger than 5 μm in the total population is less than 0.1%. In particular, it describes aqueous nanosuspensions comprising 2-15% of a substituted pteridine and at least 0.1% Tween 80 wherein the average particle diameter is in a range from 200 to 800 nm. It also teaches that for special tetracaine compositions with a low (1%) drug concentration, nanosuspensions with an average particle size of 91 nm may be obtained.
U.S. Pat. No. 5,922,355 discloses preparing microparticles of a water-insoluble or poorly soluble compound by, prior to or during reducing particle size (e.g. by sonication, homogenization, milling, microfluidization and precipitation, or recrystallization and antisolvent precipitation), mixing said particles with (a) a phospholipid and (b) at least one surfactant such that the concentration of phospholipid and surface modifier in the suspension or solid form is in the range of 0.1 to 50%, and thereafter applying energy to the mixture. It specifically describes drug formulations wherein the drug concentration is from 2 to 5%, wherein the mean particle size is between 35 and 98 nm and wherein there is no substantial variation in the mean particle size after one or more weeks storage of the formulations at 4° C.
U.S. Pat. No. 6,221,400 discloses nanocrystalline formulations of HIV protease inhibitors wherein the average particle size is below 400 nm. It specifically describes nanoparticulate compositions of indinavir wherein the mean size of the nanoparticles is between 127 and 267 nm.
International Patent application WO 02/055059 discloses methods involving both a water-miscible first solvent and an aqueous second solvent for preparing sub-micron sized particles of an organic compound. Using these methods, suspensions preparations wherein the average particle diameter is in the range from 180 to 700 nm.
Thus a common feature of the prior art publications is that it is extremely difficult to obtain drug suspensions wherein the average particle size is within the nanometer range, preferably below 500 nm. This was apparently achieved only in very specific drugs, provided further that the drug concentration in the suspension is low, e.g. below 5% by weight.
Because it is a sparingly water-soluble, normally crystalline active agent, itraconazole has attracted many attempts to improve its bioavailability. For instance, U.S. Pat. No. 6,346,533 discloses a method for obtaining itraconazole in an amorphous form exhibiting an improved bioavailability and having a particle diameter 0.5 to 10 μm. U.S. Pat. No. 6,497,905 discloses converting crystalline itraconazole into its amorphous form as a solid solution of a normally hydrophobic vehicle such as glyceryl monastearate, a monoglyceride, a diglyceride, a triglyceride, or a wax. This solid solution may be used as a component of a granular particle wherein itraconazole is present at about 5 to 60% by dry weight. Particle size of this granular particle is not specified.
International Patent application WO 2004/043580 discloses an emulsification method comprising flowing, conducting or circulating a pre-mix of two or more immiscible liquids, said pre-mix preferably comprising at least a hydrophilic liquid and at least a lipophilic liquid, through one or more magnetic fields under conditions to emulsify the said pre-mix. Although emulsions prepared according to this method may be included into veterinary or pharmaceutical compositions, this document does not refer to the solubilization of poorly soluble drugs as such.
There is a growing need in the art for improving the bioavailability in animals and in man for a number of bioactive compounds of various therapeutic groups because the water-solubility of these compounds is too low.